Chlamydia trachomatis is the leading cause of bacterial sexually transmitted infections worldwide, with annual related costs exceeding $2 billion. In women, untreated infections may progress to serious reproductive tract sequela. Chlamydiae to not appear to express proteins that actively induce disease or tissue damage in the infected host. Rather, the pathology that follows chlamydial infection is the consequence of an aggressive host inflammatory response. Using the C. muridarum mouse model, we have shown that the innate pathogen recognition receptor, TLR2, is essential for development of oviduct pathology. TLR2 gene knock-out (KO) mice do not develop oviduct pathology after chlamydial infection. In addition, plasmid-deficient C. muridarum that cause an infection in mice of normal intensity and duration fail to cause oviduct disease and do not stimulate TLR2. Our data indicate that in the presence of TLR2 signaling, chlamydial infection elicits an immune response of greater magnitude than what is needed and subsequently leads to tissue pathology. In this application we propose to validate our novel model of chlamydial disease where pathology occurs in response to primary chlamydial infection by one or both of the following paths: 1) TLR2-mediated hyper-activation of innate immune cells leading to a response that exceeds what is required for bacterial clearance, ultimately promoting excessive tissue damage and scarring; 2) TLR2-mediated hyper-activation of the CD4 T cell response. In addition, we propose to advance our studies beyond the mouse by investigating chlamydial-induced TLR2 signaling and consequential inflammatory responses in human reproductive tract tissues. Completion of our studies will allow us to determine: (1) the effect of chlamydia-induced TLR2-dependent signaling on murine innate immune cell activation in vitro and in vivo, (2) the mechanism by which mouse T cells respond to and resolve a Chlamydia infection without producing oviduct tissue damage, (3) the contribution of chlamydia-induced TLR2 activation to the inflammatory response of human reproductive tract tissue.